The pathophysiology of the acquired extracellular matrix alterations, like non-enzymatic glycosylation (NEG) of proteins secondary to diabetes or ageing, is not well characterized, particularly considering its relationship with leukocytes. We have analysed the influence of collagen NEG on the fundamental function of phagocytic cells, i.e. the production of reactive oxygen species (ROS). To this aim, we considered the activity of polymorphonuclear leukocytes and monocytes incubated in the presence of both non-glycated and glycated collagen. ROS production was monitored by chemi-luminescence (CL), a standardized and sensitive assay of phagocytes oxidative metabolism. All experiments were performed in triplicate on collagen-coated and glycated collage-coated vials. Results showed that PMNs ROS metabolism appeared unrelated to the glycation state of the substrate. Conversely, data regarding zymosan-induced CL by monocytes indicated a significant and intriguing decrease in reactive oxygen metabolism, which appeared greatly compromised by the glycation state of the matrix (monocytes in collagen, 197.4 +/- 31.2 vs. monocytes in glycated collagen, 138.0 +/- 20.4; p < 0.001 expressed as counts/cell/60 min). These data highlight the different role of polymophonuclear and monocytic phagocytes in the pathophysiology of the acquired extracellular matrix alteration secondary to non-enzymatic glycosylation (NEG) of proteins.